lactase persistence

What are the 3 main objectives of this case study?

Understand the role of general and specific transcription factors in eukaryotic gene regulation; understand how mutations in regulatory regions can affect traits; review gene expression.

What is the central dogma using the lactase gene?

DNA (LCT gene) → transcription → mRNA → translation → lactase protein.

What does it mean if the lactase gene is “turned on”?

The LCT gene is actively transcribed, producing mRNA that is translated into lactase protein.

What does it mean if the lactase gene is “turned off”?

Transcription of LCT is greatly reduced or stopped, resulting in lower levels of lactase protein.

Why do mammals typically turn off the lactase gene after weaning?

Milk is mainly needed during infancy, so mammals normally decrease lactase production after weaning when milk is no longer their main food.

What is a transcription factor?

A protein that binds specific DNA sequences and regulates whether, and how strongly, a gene is transcribed.

What is the promoter?

A regulatory DNA region where transcription machinery and general transcription factors assemble to begin transcription.

What is the TATA box?

A DNA sequence in some eukaryotic promoters that helps transcription factors recognize and initiate transcription at the promoter.

What do general transcription factors do?

They help assemble the transcription machinery at the promoter and are required for transcription initiation.

What do activators do?

Activators are specific transcription factors that increase gene transcription by helping recruit or stabilize transcription machinery.

What is an enhancer?

A regulatory DNA sequence where activator proteins bind to increase transcription of a gene.

What is special about the lactase gene’s regulation?

A specific transcription-factor activator is needed for lactase expression, and its activity is influenced by an enhancer.

How large is the lactase gene?

The lactase gene is about 55,000 base pairs long.

How long is the lactase protein?

The lactase protein is 1,927 amino acids long.

How many nucleotides are needed to code for 1,927 amino acids?

5,781 nucleotides, because each amino acid is coded for by a three-nucleotide codon.

Why is the lactase gene much longer than the sequence needed to code for the protein?

The gene contains noncoding regions in addition to the protein-coding sequence.

What is lactase persistence?

The ability to continue producing lactase after weaning and therefore digest milk and other dairy products during adulthood.

What percentage of humans produce lactase after weaning?

About 35% of humans produce lactase after weaning and are therefore lactase persistent.

What happens when lactose is not digested?

Undigested lactose enters the large intestine, where it causes the symptoms associated with lactose intolerance.

Why does undigested lactose cause cramping and diarrhea?

The increased sugar concentration creates an osmotic gradient that draws water into the large intestine.

Why does undigested lactose cause gas and flatulence?

Bacteria in the large intestine digest lactose and produce gaseous by-products such as methane, carbon dioxide, and hydrogen.

What is a SNP?

A single-nucleotide polymorphism (SNP) is a mutation in which one nucleotide, or “letter,” of DNA is changed.

What type of mutation is associated with lactase persistence?

A single-nucleotide polymorphism (SNP) in an enhancer region that regulates lactase gene expression.

Where is the mutation associated with lactase persistence located?

It is located in an enhancer sequence upstream of the lactase (LCT) gene.

Why can a single SNP have a major effect on a trait?

A SNP can change how strongly a transcription factor or activator binds to DNA, changing how much a gene is expressed.

How does the lactase-persistence SNP affect gene expression?

The mutation increases binding of the activator Oct1 to the enhancer, increasing activity of the lactase promoter.

What is Oct1?

Oct1 is a specific transcription-factor activator that binds the lactase enhancer and increases lactase promoter activity.

How does the lactase-persistence mutation affect Oct1?

The enhancer mutation increases Oct1 binding to the enhancer region.

How does increased Oct1 binding affect transcription?

Oct1 attracts more general transcription factors to the lactase gene, increasing transcription.

What happens to transcription-factor activity in wildtype adults after weaning?

Transcription-factor activity at the lactase gene decreases after weaning.

What happens when transcription-factor activity decreases after weaning?

Decreased transcription-factor activity leads to decreased transcription of the lactase gene.

What happens when lactase gene transcription decreases?

Lactase levels in enterocytes decrease, making the individual unable to efficiently digest lactose in milk.

What happens in a wildtype adult mammal?

After weaning, transcription-factor activity decreases → LCT transcription decreases → lactase levels decrease → lactose digestion decreases.

What happens in a lactase-persistent adult?

The enhancer mutation increases Oct1 binding → more transcription factors are recruited → LCT transcription stays high → lactase remains available.

How does the lactase-persistence mutation prevent the normal decrease in lactase?

Increased Oct1 binding attracts more general transcription factors, maintaining LCT transcription throughout adulthood.

What is the final effect of increased LCT transcription?

Steady levels of lactase remain in enterocytes, allowing the individual to digest lactose throughout adulthood.

Compare wildtype and lactase-persistent individuals.

Wildtype: decreased TF activity → decreased LCT transcription → low lactase. LP: increased Oct1 binding → continued transcription → steady lactase.

Why is the lactase-persistence mutation considered a regulatory mutation?

It occurs in an enhancer and changes gene expression rather than changing the amino-acid sequence of the lactase protein.

How can mutations in regulatory regions affect traits?

They can change transcription-factor binding and therefore alter how much protein a gene produces, affecting the phenotype.

Why have lactase-persistence mutations appeared in multiple regions of the world?

Similar mutations affecting the enhancer arose independently in multiple regions, showing convergent evolution.

What is the overall molecular pathway for lactase persistence?

Enhancer SNP → increased Oct1 binding → increased general TF recruitment → increased LCT transcription → continued lactase production → lactose digestion.

What is positive selection?

Natural selection favoring an advantageous trait, causing that trait to become more common in a population.

What is negative selection?

Natural selection against a disadvantageous trait, causing that trait to become less common in a population.

Why could lactase persistence provide an individual advantage?

Milk provides protein, fat, sugar, vitamins, nutrition, and hydration and can remain available despite cold weather or poor crops.

How could lactose intolerance create a disadvantage?

Non-lactase-persistent individuals could experience painful and dehydrating symptoms and miss an important source of nutrition and hydration.

How did culture contribute to the evolution of lactase persistence?

Pastoralism provided regular access to milk, creating an environment where the ability to digest milk as an adult could be advantageous.

What is the most important connection between genetics and evolution in this case?

A regulatory SNP changed gene expression, producing the lactase-persistence trait, which could then be favored by natural selection.